The limited efficiency of medical countermeasures against poisoning by nerve agent justifies efforts to find new prophylactic means and new antidotes. The concept of bioscavengers has emerged as an alternative approach to pharmacological pre- and post-exposure treatments. Catalytic scavengers are enzymes displaying a turnover with OPs as substrates, allowing rapid and efficient protection using administration of small doses. Several reasons have endorsed human paraoxonase (PON1) to be a pertinent candidate as catalytic bioscavenger. The physiological function of PON1 has not yet been unambiguously identified. Considered as a promiscuous enzyme, PON1 appears to be primarily a lactonase and also displays an anti-atherogenic activity closely linked to its localization on HDL particles. A HDL-associated phosphate transporter termed human phosphate binding protein (HPBP) was found to be a partner of natural human PON. In the absence of its natural environment (or mimicry by detergents), human PON1 is unstable and tends to aggregate. Converging data indicate that both the activity and the stability of PON1 are dramatically dependent on the HDL component molecular environment, including HPBP. Therefore, biochemical and physiological characterization of PON1-HPBP complexes, the environment allowing retaining functional enzyme state(s), and the thermal and storage stability of PON1 are mandatory. Synergistic efforts on characterization of recombinant hybrid PON1 expressed in E. coli and natural human PON1 provide information for the future rational design of stable mutants of PON1-based catalytic scavengers to be used as safe and effective countermeasures to OP intoxication.